Our objective is to understand the role of the gastrointestinal tract in producing satiety. We have shown that rats equipped with gastric fistulas sham-feed liquid food continuously: they do not display satiety. Infusion of liquid food into the duodenum during otherwise continuous sham-feeding stops sham-feeding and elicits the full behavioral display characteristic of normal satiety in the rat. Therefore, the small intestine is the site of origin of at least one potent satiety signal. We have also shown that intraperitoneal injections (in rats) and intravenous infusions (in rhesus monkeys) of the intestinal hormone cholecystokinin (CCK) decrease food intake at a test meal without producing detectable illness. Therefore, CCK may be a physiological intestinal satiety signal. Using rhesus monkeys equipped with (1) gastric fistulas (to obtain sham-feeding), (2) duodenal cannulas (to introduce food directly into the intestine), (3) gallbladder cannulas (to measure pressure changes) and (4) intraportal venous catheters (to infuse exogenous CCK or its fully active synthetic octapeptide--SQ19844--and to withdraw blood samples), we will compare the amounts of exogenous and endogenous CCK required to produce gallbladder contractile responses (the criterion for a physiological action of CCK) with the amounts required to produce satiety. These comparisons will indicate whether the satiety action of CCK is physiological or pharmacological. In a second group of experiments, we will determine whether CCK is necessary for satiety in the rat by attempting to block the satiety action of (1) CCK and its synthetic octapeptide during sham-feeding, (2) intestinally-perfused food during sham-feeding, and (3) normally ingested food, using the low-activity desulfated octapeptide analogue (SQ19,265) as the blocking agent. In a third group of experiments, we will identify the peripheral and/or central sites of action of CCK in the rat by a variety of methods: (1) parasympathetic and sympathetic gut denervations, (2) intravenous infusions of other gut hormones besides CCK, singly and in combination, (3) radio-active labelling and tracing of CCK and the octapeptide, (4) intracerebral injections of CCK and the octapeptide, and (5) electrical brain lesions.